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枝孢菌素A通过活性氧介导的自噬流触发人乳腺癌细胞的凋亡敏感性。

Cladosporol A triggers apoptosis sensitivity by ROS-mediated autophagic flux in human breast cancer cells.

作者信息

Koul Mytre, Kumar Ashok, Deshidi Ramesh, Sharma Vishal, Singh Rachna D, Singh Jasvinder, Sharma Parduman Raj, Shah Bhahwal Ali, Jaglan Sundeep, Singh Shashank

机构信息

Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.

Academy of Scientific & Innovative Research (AcSIR), CSIR, New Delhi, India.

出版信息

BMC Cell Biol. 2017 Jul 20;18(1):26. doi: 10.1186/s12860-017-0141-0.

DOI:10.1186/s12860-017-0141-0
PMID:28728544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5520384/
Abstract

BACKGROUND

Endophytes have proven to be an invaluable resource of chemically diverse secondary metabolites that act as excellent lead compounds for anticancer drug discovery. Here we report the promising cytotoxic effects of Cladosporol A (HPLC purified >98%) isolated from endophytic fungus Cladosporium cladosporioides collected from Datura innoxia. Cladosporol A was subjected to in vitro cytotoxicity assay against NCI60 panel of human cancer cells using MTT assay. We further investigated the molecular mechanism(s) of Cladosporol A induced cell death in human breast (MCF-7) cancer cells. Mechanistically early events of cell death were studied using DAPI, Annexin V-FITC staining assay. Furthermore, immunofluorescence studies were carried to see the involvement of intrinsic pathway leading to mitochondrial dysfunction, cytochrome c release, Bax/Bcl-2 regulation and flowcytometrically measured membrane potential loss of mitochondria in human breast (MCF-7) cancer cells after Cladosporol A treatment. The interplay between apoptosis and autophagy was studied by microtubule dynamics, expression of pro-apoptotic protein p21 and autophagic markers monodansylcadaverine staining and LC3b expression.

RESULTS

Among NCI60 human cancer cell line panel Cladosporol A showed least IC value against human breast (MCF-7) cancer cells. The early events of apoptosis were characterized by phosphatidylserine exposure. It disrupts microtubule dynamics and also induces expression of pro-apoptotic protein p21. Moreover treatment of Cladosporol A significantly induced MMP loss, release of cytochrome c, Bcl-2 down regulation, Bax upregulation as well as increased monodansylcadaverine (MDC) staining and leads to LC3-I to LC3-II conversion.

CONCLUSION

Our experimental data suggests that Cladosporol A depolymerize microtubules, sensitize programmed cell death via ROS mediated autophagic flux leading to mitophagic cell death. The proposed mechanism of Cladosporol A -triggered apoptotic as well as autophagic death of human breast cancer (MCF-7) cells. The figure shows that Cladosporol A induced apoptosis through ROS mediated mitochondrial pathway and increased p21 protein expression in MCF-7 cells in vitro.

摘要

背景

内生菌已被证明是化学结构多样的次生代谢产物的宝贵资源，这些次生代谢产物可作为抗癌药物发现的优良先导化合物。在此，我们报告了从曼陀罗中采集的内生真菌枝孢霉中分离得到的枝孢菌素A（HPLC纯化>98%）具有显著的细胞毒性作用。使用MTT法对枝孢菌素A进行了针对NCI60人癌细胞系的体外细胞毒性测定。我们进一步研究了枝孢菌素A诱导人乳腺癌（MCF-7）细胞死亡的分子机制。使用DAPI、膜联蛋白V-FITC染色法研究了细胞死亡的早期机制。此外，进行了免疫荧光研究，以观察枝孢菌素A处理后人乳腺癌（MCF-7）细胞中导致线粒体功能障碍、细胞色素c释放、Bax/Bcl-2调节以及流式细胞术检测的线粒体膜电位丧失的内在途径的参与情况。通过微管动力学、促凋亡蛋白p21的表达以及自噬标记物单丹磺酰尸胺染色和LC3b表达研究了凋亡与自噬之间的相互作用。

结果

在NCI60人癌细胞系中，枝孢菌素A对人乳腺癌（MCF-7）细胞的IC值最低。凋亡的早期事件以磷脂酰丝氨酸暴露为特征。它破坏微管动力学并诱导促凋亡蛋白p21的表达。此外，枝孢菌素A处理显著诱导线粒体膜电位丧失、细胞色素c释放、Bcl-2下调、Bax上调以及单丹磺酰尸胺（MDC）染色增加，并导致LC3-I向LC3-II转化。

结论

我们的实验数据表明，枝孢菌素A使微管解聚，通过ROS介导的自噬通量使程序性细胞死亡敏感化，导致线粒体自噬性细胞死亡。提出了枝孢菌素A触发人乳腺癌（MCF-7）细胞凋亡以及自噬性死亡的机制。图显示枝孢菌素A在体外通过ROS介导的线粒体途径诱导MCF-7细胞凋亡并增加p21蛋白表达。

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